TY - JOUR
T1 - SMAC mimetics as potential cancer therapeutics in myeloid malignancies
AU - Boddu, Prajwal
AU - Carter, Bing Z.
AU - Verstovsek, Srdan
AU - Pemmaraju, Naveen
N1 - Funding Information:
NP: research funding and research support: Novartis, Stem-line, Abbvie, Samus, Cellectis, Daiichi Sankyo, Plexxikon; NP also has research funding from SagerStrong Foundation.
Funding Information:
This study was supported by University of Texas MD Anderson Cancer Center Support Grant P30 CA16672 and by the Leukemia SPORE Grant (P50 CA100632).
Publisher Copyright:
© 2019 British Society for Haematology and John Wiley & Sons Ltd
PY - 2019/4
Y1 - 2019/4
N2 - Evasion of apoptosis has been identified as one of the essential hallmarks of cancer. Inhibitor of apoptosis proteins (IAPs) are implicated in a host of myeloid malignancies, providing the rationale for strategies aimed at neutralizing IAPs to lower the cancer cell apoptosis threshold. Modes of IAP antagonism may include down-regulating IAP expression, up-regulating endogenous pro-apoptotic proteins, such as tumour necrosis factor-α or Fas ligand, or directly antagonizing IAP activity against caspases. Direct targeting of IAPs using mimetics of the second mitochondria-derived activator of caspase (SMAC) protein has shown therapeutic promise by sensitizing the effect of chemotherapy on malignant cells. In pre-clinical studies, SMAC mimetics have demonstrated broad synergistic activity with a wide range of therapeutics, including cytotoxic chemotherapy, receptor tyrosine kinase inhibitors, agents targeting death receptors and alternative mechanisms of cell death, such as necroptosis or autophagy and immune check point blockade. SMAC mimetics represent a novel approach for further investigation in patients with high-risk, chemo-refractory blood cancers, as single agents or in thoughtfully selected combinations. In this review, we discuss the development and therapeutic rationale of small molecule SMAC mimetics, with an emphasis on agents in clinical development for myeloid malignancies.
AB - Evasion of apoptosis has been identified as one of the essential hallmarks of cancer. Inhibitor of apoptosis proteins (IAPs) are implicated in a host of myeloid malignancies, providing the rationale for strategies aimed at neutralizing IAPs to lower the cancer cell apoptosis threshold. Modes of IAP antagonism may include down-regulating IAP expression, up-regulating endogenous pro-apoptotic proteins, such as tumour necrosis factor-α or Fas ligand, or directly antagonizing IAP activity against caspases. Direct targeting of IAPs using mimetics of the second mitochondria-derived activator of caspase (SMAC) protein has shown therapeutic promise by sensitizing the effect of chemotherapy on malignant cells. In pre-clinical studies, SMAC mimetics have demonstrated broad synergistic activity with a wide range of therapeutics, including cytotoxic chemotherapy, receptor tyrosine kinase inhibitors, agents targeting death receptors and alternative mechanisms of cell death, such as necroptosis or autophagy and immune check point blockade. SMAC mimetics represent a novel approach for further investigation in patients with high-risk, chemo-refractory blood cancers, as single agents or in thoughtfully selected combinations. In this review, we discuss the development and therapeutic rationale of small molecule SMAC mimetics, with an emphasis on agents in clinical development for myeloid malignancies.
KW - LCL-161
KW - Myelofibrosis
KW - Myeloproliferative Neoplasms
KW - SMAC
KW - inhibitor of apoptosis protein
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U2 - 10.1111/bjh.15829
DO - 10.1111/bjh.15829
M3 - Review article
C2 - 30836448
AN - SCOPUS:85062499469
SN - 0007-1048
VL - 185
SP - 219
EP - 231
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 2
ER -